The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at University of California, Los Angeles, CA.
Am J Transplant. 2017 Oct;17(10):2572-2579. doi: 10.1111/ajt.14290. Epub 2017 May 9.
Vascularized composite allotransplantation (VCA) is a viable reconstructive option for complex tissue defects. Although grafts with a large muscular component may be uniquely susceptible to ischemia-reperfusion (I/R) syndrome, the safe cold ischemia time in VCA has not been established. We investigated the effects of cold ischemia on innate immune response and recipient survival in a murine orthotopic hindlimb transplantation model. Surprisingly, mice receiving grafts exposed to 6 h or longer of cold storage demonstrated reduced survival and massive elevations in serum creatinine, blood urea nitrogen, and creatine kinase, compared with 1 h of cold storage recipients. This was accompanied by progressive increase in macrophage and neutrophil cell infiltration in muscle biopsy specimens, altered platelet endothelial cell adhesion molecule-1 expression, and ultimate renal injury. Multiplex immunoassay analysis identified 21 cytokines in serum and 18 cytokines in muscle biopsy specimens that are likely essential in the complex response to I/R-triggered injury in VCA. In conclusion, this study, in a mouse model of orthotopic hindlimb transplantation, is the first to document that prolonged cold ischemia triggers progressive I/R injury with vascular endothelial damage and may lead to irrecoverable local and remote organ damage. These experimental findings are important in guiding future therapies for human VCA recipients.
血管化复合组织移植（VCA）是治疗复杂组织缺损的可行重建选择。尽管含有大肌肉成分的移植物可能特别容易受到缺血再灌注（I/R）综合征的影响，但 VCA 中的安全冷缺血时间尚未确定。我们在同种异体小鼠后肢移植模型中研究了冷缺血对固有免疫反应和受体存活的影响。令人惊讶的是，与接受 1 小时冷储存的受体相比，接受 6 小时或更长时间冷储存的移植物的小鼠表现出存活率降低和血清肌酐、血尿素氮和肌酸激酶水平的大量升高。这伴随着肌肉活检标本中巨噬细胞和中性粒细胞浸润的逐渐增加、血小板内皮细胞黏附分子-1 表达的改变以及最终的肾损伤。多重免疫分析在血清中鉴定出 21 种细胞因子，在肌肉活检标本中鉴定出 18 种细胞因子，这些细胞因子可能在 VCA 中 I/R 触发损伤的复杂反应中是必不可少的。总之，这项在同种异体小鼠后肢移植模型中的研究首次证明，长时间的冷缺血会引发渐进性的 I/R 损伤，导致血管内皮损伤，并可能导致不可逆转的局部和远处器官损伤。这些实验结果对于指导未来人类 VCA 受者的治疗方法非常重要。
